Acetylenes disubstituted with a 5 substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity

ABSTRACT

Compounds of the formula ##STR1## wherein the symbols R 1 , R 2 , R 3 , R 19 , Y, A, B, m and o have the meaning described in the specification have retinoid like biological activity.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of application Ser. No.08/366,168, filed on Dec. 29, 1994, to be issued as U.S. Pat. No.5,514,825.

FIELD OF THE INVENTION

The present invention relates to novel compounds having retinoid-likeactivity. More specifically, the present invention relates to compoundshaving an acetylene portion which is substituted with a 5 substitutedtetrahydronaphthyl and by a substituted aryl or substituted heteroarylgroup having an acid function. The acid function may also be convertedto an alcohol, aldehyde or ketone or derivatives thereof, or may bereduced to --CH₃.

BACKGROUND ART

Compounds which have retinoid-like activity are well known in the art,and are described in numerous United States and other patents and inscientific publications. It is generally known and accepted in the artthat retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil®, diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

U.S. Pat. Nos. 4,740,519 (Shroot et al.), 4,826,969 (Maignan et al.),4,326,055 (Loeliger et al.), 5,130,335 (Chandraratna et al.), 5,037,825(Klaus et al.), 5,231,113 (Chandraratna et al.), 5,324,840(Chandraratna), Published European Patent Application Nos. 0 176 034 A(Wuest et al.), 0 350 846 A (Klaus et al.), 0 176 032 A (Frickel etal.), 0 176 033 A (Frickel et al.), 0 253 302 A (Klaus et al.), 0 303915 A (Bryce et al.), UK Patent Application GB 2190378 A (Klaus et al.),German Patent Application Nos. DE 3715955 A1 (Klaus et al.), DE 3602473A1 (Wuest et al., and the articles J. Amer. Acad. Derm. 15: 756-764(1986) (Sporn et al.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo etal.), J. Med Chem. 1988 31, 2182-2192 (Kagechika et al.), Chemistry andBiology of Synthetic Retinoids CRC Press Inc. 1990 p 334-335, 354(Dawson et al.), describe or relate to compounds which include atetrahydronaphthyl moiety and have retinoid-like or related biologicalactivity. U.S. Pat. No. 4,391,731 (Boller et al.) describestetrahydronaphthalene derivatives which are useful in liquid crystalcompositions. Several co-pending applications and recently issuedpatents which are assigned to the assignee of the present application,are directed to further compounds having retinoid-like activity.

SUMMARY OF THE INVENTION

The present invention covers compounds of Formula 3 ##STR2## wherein R₁is hydrogen or alkyl of 1 to 10 carbons; R₂ and R₃ are hydrogen, oralkyl of 1 to 6 carbons and the substituted ethynyl group occupieseither the 2 or the 3 position of the tetrahydronaphthalene nucleus;

m is an integer having the value of 0-3;

o is an integer having the value 0-4;

Y is a phenyl group, or heteroaryl selected from a group consisting ofpyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, said groups being optionally substituted withone or two R₂ groups;

A is (CH₂)_(n) where n is 0-5, lower branched chain alkyl having 3-6carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds;

B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or tri-lower alkylsilyl, where R₇ isan alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ isan alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons, and

R₁₉ is independently hydrogen, alkyl of 1 to 10 carbons,fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbonsand having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to3 triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁ -C₁₀ -alkylphenyl, naphthyl, C₁ -C₁₀ -alkylnaphthyl,phenyl-C₁ -C₁₀ alkyl, naphthyl-C₁ -C₁₀ alkyl; CN, CHO, CH(OR₁₂)₂, CHOR₁₃O, (CH₂)_(p) CO₂ R₈, (CH₂)_(p) CH₂ OH, (CH₂)_(p) CH₂ OR₁₁, (CH₂)_(p) CH₂OCOR₁₁, where p is an integer between 0 to 10, or the two R₁₉ groupsjointly represent 3 to 6 methylene groups which together with thealkylidene carbon complete a ring.

In a second aspect, this invention relates to the use of the compoundsof Formula 3 for the treatment of skin-related diseases, including,without limitation, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsare also useful for the prevention and treatment of cancerous andprecancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withHuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil®, diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 3 in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to processes for making acompound of Formula 3 which process comprises reacting a compound ofFormula 8 with a compound of Formula 9, in the presence of cuprousiodide and Pd(PQ₃)₂ Cl₂ (Q is phenyl) or a similar complex, or reactingthe zinc salt of the compound shown in Formula 8 with a compound ofFormula 9 in the presence of Pd(PQ₃)₄ (Q is phenyl) or similar complex.In Formula 8 the symbol STHN (substituted tetrahydronaphthyl) representsa tetrahydronaphthalene nucleus which is appropriately substituted toprovide the compounds defined in Formula 3 or said tetrahydronaphthalenenucleus is appropriately substituted to provide such precursors ofcompounds of Formula 3 from which the target compounds can be readilyobtained by organic reactions well known in the art. In Formula 9 X₁ ishalogen, B' is H, or a protected acid, alcohol, aldehyde, or ketone. Ineffect, B' is either the desired B group of Formula 3 or B' is aprecursor from which the B group can be readily obtained by reactionswell known in the art. ##STR3##

Still further, the present invention relates to such reactions performedon the compounds of Formula 3 which cause transformations of the A--Bgroup or of the substituents on the tetrahydronaphthalene moiety, whilethe reaction product still remains within the scope of Formula 3.

General Embodiments

Definitions

The term alkyl refers to and covers any and all groups which are knownas normal alkyl, branched-chain alkyl and cycloalkyl. The term alkenylrefers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

Lower alkyl means the above-defined broad definition of alkyl groupshaving 1 to 6 carbons in case of normal lower alkyl, and as applicable 3to 6 carbons for lower branch chained and cycloalkyl groups. Loweralkenyl is defined similarly having 2 to 6 carbons for normal loweralkenyl groups, and 3 to 6 carbons for branch chained and cyclo-loweralkenyl groups. Lower alkynyl is also defined similarly, having 2 to 6carbons for normal lower alkynyl groups, and 4 to 6 carbons for branchchained lower alkynyl groups.

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. It includes organic and inorganic esters. Where B (of Formula3) is --COOH, this term covers the products derived from treatment ofthis function with alcohols or thiols preferably with aliphatic alcoholshaving 1-6 carbons. Where the ester is derived from compounds where B is--CH₂ OH, this term covers compounds derived from organic acids capableof forming esters including phosphorous based and sulfur based acids, orcompounds of the formula --CH₂ OCOR₁₁ where R₁₁ is any substituted orunsubstituted aliphatic, aromatic, heteroaromatic or aliphatic aromaticgroup, preferably with 1-6 carbons in the aliphatic portions.

Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Unless statedotherwise in this application, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

Acetals and ketals include the radicals of the formula-CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₇ O-- where R₇ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compounds inthis invention having a functionality capable of forming such salt, forexample an acid functionality. A pharmaceutically acceptable salt is anysalt which retains the activity of the parent compound and does notimpart any deleterious or untoward effect on the subject to which it isadministered and in the context in which it is administered.

Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri- acid may also be used.

Some of the compounds of the present invention may have trans and cis (Eand Z) isomers. In addition, the compounds of the present invention maycontain one or more chiral centers and therefore may exist inenantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all such isomers per se, as well asmixtures of cis and trans isomers, mixtures of diastereomers and racemicmixtures of enantiomers (optical isomers) as well. In the presentapplication when no specific mention is made of the configuration (cis,trans or R or S) of a compound (or of an asymmetric carbon) then amixture of such isomers, or either one of the isomers is intended. In asimilar vein, when in the chemical structural formulas of thisapplication a straight line representing a valence bond is drawn to anasymmetric carbon, then isomers of both R and S configuration, as wellas their mixtures are intended. Defined stereochemistry about anasymmetric carbon is indicated in the formulas (where applicable) by asolid triangle showing β configuration, or by a hashed line showing αconfiguration.

Referring now to the nomenclature used in naming the compounds of theinvention and intermediate compounds leading thereto, two differentsystems for numbering the tetrahydronaphthalene ring are demonstrated asshown by the structural formulas of Compounds F, G and 1. Compound 1 andCompounds F and G are exemplary intermediates utilized in the synthesisof the compounds of the invention. The numbering systems illustratedhere will not only be readily apparent to those skilled in the art, butwill be readily understood as it is applied in the ensuing descriptionof the compounds of the invention and of intermediates utilized forobtaining the compounds of the invention. ##STR4##

With reference to the symbol Y in Formula 3, the preferred compounds ofthe invention are those where Y is phenyl, pyridyl, thienyl or furyl.Even more preferred are compounds where Y is phenyl or pyridyl. As faras substititutions on the Y (phenyl) and Y (pyridyl) groups areconcerned, compounds are preferred where the phenyl group is 1,4 (para)substituted, and where the pyridine ring is 2,5 substituted.(Substitution in the 2,5 positions in the "pyridine" nomenclaturecorresponds to substitution in the 6-position in the "nicotinic acid"nomenclature.) In the preferred compounds of the invention there is nooptional R₂ substituent on the Y group.

The A--B group of the preferred compounds is (CH₂)_(n) --COOH or(CH₂)_(n) --COOR₈ where R₈ is defined as above. Even more preferably nis zero and R₈ is lower alkyl.

Referring still to the preferred compounds of Formula 3, the aromaticportion of the tetrahydronaphthalene moiety is preferably substitutedonly by the acetylene function. In other words, in the preferredcompounds there is no R₂ substituent (other than hydrogen). Similarly,in the preferred compounds of the invention there is no R₃ substituent(other than hydrogen). The R₁ substituent of the compounds of theinvention is preferably lower alkyl, and even more preferably methyl.

The R₁₉ groups of the compounds of the invention preferably arehydrogen, alkyl of 1 to 10 carbons, cyano (CN) or COOR₈. Even morepreferably the R₁₉ groups are H, CN, COOEt or lower alkyl.Alternatively, in the preferred compounds of the invention in accordancewith Formula 3 the two R₁₉ groups jointly form a --(CH₂)_(q) -- radical,(q is an integer having the values of 3 to 7) whereby a cycloalkyl ringis formed, most preferably a cyclohexyl ring. Specific preferredcompounds in accordance with Formula 3 and their synthesis are describedbelow in the section of this application titled "Specific Examples". Thepresently most preferred compounds of the invention in accordance withFormula 3 are indicated in Table 1 below, with reference to Formula 3A.In this Table the tetrahydronaphthalene ring is numbered as shown abovein connection with Compound 1. ##STR5##

                  TABLE 1                                                         ______________________________________                                                   Position                                                                      of                                                                            Ethynyl                                                            Compound No.                                                                             Subst.   X.sub.2 R.sub.8                                                                           R.sub.19'                                                                             R.sub.19"                             ______________________________________                                        115        2        CH      Et  H       CO.sub.2 Et                           121        3        CH      Et  H       CO.sub.2 Et                           131        2        CH      Et  (CH.sub.2).sub.5.sup.1                                                                --                                    132        3        CH      Et  (CH.sub.2).sub.5.sup.1                                                                --                                    133        2        CH      Et  Et      Et                                    134        3        CH      Et  Et      Et                                    135        2        CH      H   (CH.sub.2).sub.5.sup.1                                                                --                                    136        3        CH      H   (CH.sub.2).sub.5                                                                      --                                    137        2        CH      H   Et      Et                                    138        3        CH      H   Et      Et                                    145        2        CH      Et  CN.sup.2                                                                              H                                     146        2        CH      Et  H       CN.sup.3                              ______________________________________                                         .sup.1 The R'.sub.19 and R.sub.19 " groups jointly represent methylene        groups which together with the alkylidene carbon complete a ring having a     total of 6 carbons.                                                           .sup.2 The CN group is in the E (trans) configuration.                        .sup.3 The CN group is in Z (cis) configuration.                         

Modes of Administration

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards it expansion. In certain instances, the compoundpotentially may be used in prophylactic manner to prevent onset of aparticular condition.

A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

Assay of Retinoid-like Biological Activity

The retinoic acid-like activity of these compounds is confirmed throughthe classic measure of retinoic acid activity involving the effects ofretinoic acid on ornithine decarboxylase. The original work on thecorrelation between retinoic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37,2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcases for ODC activity increases are unknown, it is known that12-O-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. An assayessentially following the procedure set out in Cancer Research:1662-1670,1975 may be used to demonstrate inhibition of TPA induction ofODC by compounds of this invention. Activity of exemplary compounds ofthe present invention in the above-described ODC assay is disclosed inTable 2 which provides the IC₈₀ concentration for the respectiveexemplary compound. ("IC₈₀ " is that concentration of the test compoundwhich causes 80% inhibition in the ODC assay. By analogy, "IC₆₀, forexample, is that concentration of the test compound which causes 60%inhibition in the ODC assay.)

                  TABLE 2                                                         ______________________________________                                        Compound #         IC.sub.80 conc (nmols)                                     ______________________________________                                        115                3.90                                                       121                2.50                                                       131                19.10                                                      133                0.30                                                       134                10* (IC.sub.48.6)                                          145                6.60                                                       ______________________________________                                         *the inhibition shown in brackets was attained at this concentration;    

SPECIFIC EMBODIMENTS

The compounds of this invention can be made by the synthetic chemicalpathways illustrated here. The synthetic chemist will readily appreciatethat the conditions set out here are specific embodiments which can begeneralized to any and all of the compounds of the invention.

SYNTHESIS ##STR6##

Referring now to Reaction Scheme 1 a synthetic route leading toprecursors of the compounds of the invention, is illustrated. Inaccordance with this scheme, a 6- or 7-bromo substituted3,4-dihydronaphthalen-1(2H)-one (numbering as shown for Compound G) ofFormula 10 is the starting material. The compounds of Formula 10 alreadycarry the desired R₁, R₂ and R₃ substituents, as these are defined abovein connection with Formula 3. The compounds of Formula 10 are reactedwith trimethylsilylacetylene to provide the 6- or7-trimethylsilylethynyl-substituted 3,4-dihydronaphthalen-1(2H)-onecompounds of Formula 11. The reaction with trimethylsilylacetylene istypically conducted under heat (approximately 100° C.) in the presenceof cuprous iodide, a suitable catalyst, typically having the formulaPd(PPh₃)₂ Cl₂, an acid acceptor (such as triethylamine) under an inertgas (argon) atmosphere. Typical reaction time is approximately 24 hours.The 6- or 7-(trimethylsilyl)ethynyl-substituted3,4-dihydronaphthalen-1(2H)-one compounds of Formula 11 are then reactedwith base (potassium hydroxide or potassium carbonate) in an alcoholicsolvent, such as methanol, to provide the 6- or 7-ethynyl substituted3,4-dihydro-1-naphthalen-1(2H)ones of Formula 12. Compounds of Formula12 are then coupled with the aromatic or heteroaromatic reagent X₁--Y(R₂)--A--B' (Formula 9) in the presence of cuprous iodide, a suitablecatalyst, typically Pd(PPh₃)₂ Cl₂, an acid acceptor, such astriethylamine, under inert gas (argon) atmosphere. Alternatively, a zincsalt (or other suitable metal salt) of the compounds of Formula 12 canbe coupled with the reagents of Formula 9 in the presence of Pd(PPh₃)₄or similar complex. Typically, the coupling reaction with the reagent X₁--Y(R₂)--A--B' (Formula 9) is conducted at room or moderately elevatedtemperature. Generally speaking, coupling between an ethynylarylderivative or its zinc salt and a halogen substituted aryl or heteroarylcompound, such as the reagent of Formula 9, is described in U.S. Pat.No. 5,264,456, the specification of which is expressly incorporatedherein by reference. The compounds of Formula 13 when appropriatelyprotected in the B' group, can be reacted in a McMurry coupling reactionto provide compounds of the invention. The compounds of Formula 13 canalso be converted into further precursors for the compounds of theinvention by such reactions and transformations which are well known inthe art. Such reactions are indicated in Reaction Scheme 1 by conversioninto "homologs and derivatives". One such conversion employed for thesynthesis of several exemplary compounds of this invention issaponification of an ester group (when B or B' is an ester) to providethe free carboxylic acid or its salt.

The halogen substituted aryl or heteroaryl compounds of Formula 9 can,generally speaking, be obtained by reactions well known in the art. Anexample of such compound is ethyl 4-iodobenzoate which is obtainable,for example, by esterification of 4-iodobenzoic acid. Another example isethyl 6-iodonicotinoate which can be obtained by conducting a halogenexchange reaction on 6-chloronicotinic acid, followed by esterification.Even more generally speaking, regarding derivatization of compounds ofFormula 13 and/or the synthesis of aryl and heteroaryl compounds ofFormula 9 which can thereafter be reacted with compounds of Formula 12to yield compounds of the invention or precursors thereto, the followingwell known and published general principles and synthetic methodologycan be employed.

Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, "AdvancedOrganic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

To increase the value of n in the compounds of Formula 9 beforeaffecting the coupling reaction of Reaction Scheme 1 (where suchcompounds corresponding to Formula 9 are not available from a commercialsource) aromatic or heteroaromatic carboxylic acids are subjected tohomologation by successive treatment under Arndt-Eistert conditions orother homologation procedures. Alternatively, derivatives which are notcarboxylic acids may also be homologated by appropriate procedures. Thehomologated acids can then be esterified by the general procedureoutlined in the preceding paragraph.

Compounds of Formula 9, (or of the invention as set forth in Formula 3,or related intermediates, as applicable) where A is an alkenyl grouphaving one or more double bonds can be made for example, by syntheticschemes well known to the practicing organic chemist; for example byWittig and like reactions, or by introduction of a double bond byelimination of halogen from an alpha-halo-arylalkyl-carboxylic acid,ester or like carboxaldehyde. Compounds of Formula 9 (or of theinvention as set forth in Formula 3 or intermediates, as applicable)where the A group has a triple (acetylenic) bond can be made by reactionof a corresponding aromatic methyl ketone with strong base, such aslithium diisopropyl amide, reaction with diethyl chlorophosphate andsubsequent addition of lithium diisopropyl amide.

The acids and salts derived from compounds of Formula 13 (or otherintermediates, or compounds of the invention as set forth in Formula 3,as applicable) are readily obtainable from the corresponding esters.Basic saponification with an alkali metal base will provide the acid.For example, an ester of Formula 13 (or other compounds of the inventionas set forth in Formula 3) may be dissolved in a polar solvent such asan alkanol, preferably under an inert atmosphere at room temperature,with about a three molar excess of base, for example, lithium hydroxideor potassium hydroxide. The solution is stirred for an extended periodof time, between 15 and 20 hours, cooled, acidified and the hydrolysaterecovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about -10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkyl halides underWilliamson reaction conditions (March, Ibid, pg. 357) gives thecorresponding ethers. These alcohols can be converted to esters byreacting them with appropriate acids in the presence of acid catalystsor dicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds of Formula 9 (or other intermediates or of the invention asset forth in Formula 3) where B is H can be prepared from thecorresponding halogenated aromatic or hetero aromatic compounds,preferably where the halogen is I. ##STR7##

In the preferred compounds of the invention the two R₁ substituents aremethyl, and the R₂ and R₃ substituents are hydrogen. Reaction Scheme 2illustrates a synthetic process for preparing7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) whichserves as a starting material for the synthesis of several preferredcompounds of the invention. Thus, referring now specifically to ReactionScheme 2, ethyl 3-bromophenylacetate (Compound B, made by esterificationof 3-bromophenylacetic acid) is reduced with diisobutylaluminumhydride(DIBAL-H) to yield (3-bromophenyl)acetaldehyde.(3-Bromophenyl)acetaldehyde is reacted in a Wittig reaction with(carbethoxymethylene)triphenylphosphorane to provide a mixture of E andZ ethyl 4-(3-bromophenyl)but-2-enoates. The latter compounds arehydrogenated to yield ethyl 4-(3-bromophenyl)butanoate (Compound D).Compound D is reacted with the Grignard reagent derived frommethylbromide to give the tertiary alcohol5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should beapparent to those skilled in the art, that the choice of the Grignardreagent used in this reaction step determines the nature of the R₁substituent in the resulting compounds of the invention.) Compound E isthen treated with acid to cyclize it and to form6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F).Compound F is oxidized with chromium trioxide to yield7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G).Compound G is covered by Formula 10 and in accordance with ReactionSchemes 1 and 3 serves as a starting material in the synthesis ofseveral preferred compounds of the invention.

6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) isisomeric with Compound G, and can be obtained, starting with ethyl(4-bromophenyl)acetate, in accordance with the sequence of reactionsillustrated in Reaction Scheme 2 for Compound G.6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) canalso be obtained in accordance with the published literature procedure:Mathur et al. Tetrahedron, 41, 1509-1516 (1985). Compound H is alsocovered by Formula 10 and in accordance with Reaction Schemes 1 and 3serves as a starting material in the synthesis of several preferredcompounds of the invention.

Starting materials for the synthetic routes outlined in Reaction Schemes1-3 where the R₂ and/or R₃ groups are other than hydrogen, can beobtained similarly to the synthesis of the starting materialsdemonstrated in Reaction Scheme 2, and/or by introducing the R₂ by aFriedel-Crafts or like reaction into the aromatic portion of thetetrahydronaphthalene nucleus. ##STR8##

Compounds of Formula 3 are preferably synthesized in accordance with thesynthetic steps illustrated in Reaction Schemes 3, 4 and 5. Referringfirst to Reaction Scheme 3, the 1-oxo 6- or 7-bromo1,2,3,4-tetrahydronaphthalene derivative (numbering as exemplified forCompound G) of Formula 10 is reacted with a ketone or aldehyde compoundof Formula 25 wherein the R₁₉ groups are defined as in connection withFormula 3. The reaction (McMurry coupling) is conducted at elevatedtemperature in the presence of lithium metal and titanium trichloride,in an inert ether type solvent, for example in refluxing1,2-dimethoxyethane (DME). The resulting compounds of Formula 26 arethen reacted with trimethylsilylacetylene as described above inconnection with Reaction Scheme 1 (cuprous iodide, Pd(Pph₃)₂ Cl₂,catalyst and triethylamine under inert atmosphere) and thereafter withbase (potassium hydroxide or potassium carbonate in an alcoholicsolvent, such as methanol) to provide the 6- or 7-ethynyl1,2,3,4-tetrahydronaphthalene derivatives of Formula 27 which have theR₁₉ R₁₉ C═ group attached to the tetrahydronaphthalene nucleus.Compounds of Formula 27 are then coupled with the aromatic orheteroaromatic reagent X₁ --Y(R₂)--A--B' (Formula 9) in the presence ofcuprous iodide, a suitable catalyst, typically Pd(PPh₃)₂ Cl₂, an acidacceptor, such as diethylamine, under inert gas (argon) atmosphere, asdescribed above in connection with Reaction Scheme 1, to yield compoundsof Formula 28. Alternatively, as is also described in connection withthe analogous coupling reaction of Scheme 1, the zinc salts of thecompounds of Formula 27 are coupled with the reagents of Formula 9, inthe presence of Pd(PPh₃)₄ or similar complex. Compounds of Formula 28are within the scope of Formula 3. They can be converted to furtherhomologs and derivatives which are still within the scope of theinvention, as is described above in connection with compounds of Formula13. ##STR9##

Referring now to Reaction Scheme 4, synthesis of those compounds ofFormula 3 is illustrated where one of the R₁₉ groups represents hydrogenand the other is cyano (CN). These compounds are obtained by reacting a5-oxo 2- or 3-(aryl or heteroaryl)ethynyl 5,6,7,8-tetrahydronaphthalenecompound of Formula 13 (numbering as exemplified for Compound 1) withdiethyl cyanomethylphosphonate and potassium bis(trimethylsilyl)amide inan inert ether type solvent, such as tetrahydrofuran. The resultingcompounds of Formula 29 can be converted into further homologs andderivatives, as described above. Also, the cyano derivative (Formula 29)can be converted into the corresponding aldehyde by reduction withdiisobutylaluminum hydride. ##STR10##

Reaction Schema 5 illustrates synthesis of those compounds of Formula 3wherein one of the R₁₉ groups is hydrogen and the other is a carboxylicacid ester (or derivative thereof). The starting compounds for thesesyntheses are compounds of Formula 30, which can be obtained byconducting a Reformatsky reaction (reaction with an α halocarboxylicacid in the presence of zinc, under conditions well known in the art) onthe 5-oxo tetrahydronaphthalene compound of Formula 10 followed by thesynthetic steps outlined in Reaction Scheme 1. Alternatively a compoundof Formula 30 can also be obtained by conducting a Reformatsky reactionon a compound (suitably protected in the B' group) of Formula 13.Dehydration (elimination of the hydroxy group) of compounds of Formula30 with a suitable reagent such as(methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent)by heating moderately (50° C.) in an inert solvent, such as benzene,provides compounds of Formula 31 and also compounds isomeric therewithwhere the newly formed double bond is within the ring. The latterisomeric compounds are not shown in Reaction Scheme 5. The mixtures ofthese isomers are separated by chromatography or other conventionalmethods known in the art, to yield the compounds of Formula 31. Thecompounds of Formula 31 are within the scope of Formula 3, and can alsobe converted into further homologs and derivatives still within thescope of the invention.

SPECIFIC EXAMPLES

Ethyl (4-bromophenyl)acetate (Compound A)

A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g ofconc. H₂ SO₄ in 470 ml of ethanol was refluxed for 16 hours. Thereaction mixture was cooled to ambient temperature, stirred with 6 g ofsolid K₂ CO₃ for 30 minutes and then filtered. The filtrate wasconcentrated in vacuo, diluted with Et₂ O (200 ml), washed with 10%aqueous NaHCO₃ (10 ml) and brine (10 ml), dried over MgSO₄ andconcentrated in vacuo to give the title compound as a colorless oil.

PMR (CDCl₃): δ1.25 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q, J=7.0Hz), 7.16 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).

Ethyl (3-bromophenyl)acetate (Compound B)

Employing the same general procedure as for the preparation of ethyl(4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of3-bromophenylacetic acid was converted into the title compound (yellowoil) using 2 g of conc. H₂ SO₄ and 500 ml of ethanol.

PMR (CDCl₃): δ1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q, J=7.0Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).

Ethyl 4-(4-bromophenyl)butanoate (Compound C)

To a cold solution (-78° C.) of 15 g (62 mmol) of ethyl(4-bromophenyl)acetate (Compound A) in 150 ml of CH₂ Cl₂ was addeddropwise (over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminumhydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition wascomplete, the reaction was stirred at -78° C. for an additional hour.The reaction was quenched by the dropwise addition of methanol (10 ml),followed by water (10 ml) and 10% HCl (40 ml). The mixture was thenwarmed to 0° C., stirred for 10 minutes and then washed with water (15ml), 10% aqueous NaHCO₃ (10 ml) and brine (10 ml). The organic phase wasdried over MgSO₄ and the solvent distilled off at ambient temperature togive crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) ofthis crude aldehyde in 150 ml of CH₂ Cl₂ was added a solution of 26 g(74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml of CH₂Cl₂. The mixture was stirred for 16 hours, concentrated in vacuo andpurified by flash chromatography (silica, 10% EtOAc-hexane) to giveethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. Thisisomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and thefiltrate concentrated in vacuo to give the title compound as a whitesolid.

PMR (CDCl₃): δ1.26 (3H, t, J=7.1 Hz), 1.88-1.99 (2H, m), 2.31 (2H, t,J=7.5 Hz), 2.61 (2H, t, J=7.5 Hz), 4.28 (2H, q, J=7.1 Hz), 7.05 (2H, d,J=8.4 Hz), 7.40(2H, d, J=8.4 Hz).

Ethyl 4-(3-bromophenyl)butanoate (Compound D)

Employing the same general multistep preparation as for ethyl4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl(3-bromophenyl)acetate (Compound B) was converted into the titlecompound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride(DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of(carbethoxymethylene)triphenylphosphorane and 1.7 g of 10% Pd/C.

PMR (CDCl₃): δ1.26 (3H, t, J=7.1 Hz), 1.89-2.00 (2H, m), 2.31 (2H, t,J=7.5 Hz), 2.63 (2H, t, J=7.2 Hz), 4.15 (2H, q, J=7.1 Hz), 7.10-7.35(4H, m).

5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)

To a cold solution (0° C.) of 17 g (63 mmol) of ethyl4-(3-bromophenyl)butanoate (Compound D) in 40 ml of THF was added 63 ml(189 mmol) of methylmagnesium bromide (3.0M solution in THF). Thereaction was stirred at 0° C. for 2 hours, quenched by the slow additionof ice cold water (30 ml) followed by 10% HCl (30 ml) and then extractedwith Et₂ O (4×60 ml). The combined organic layer was washed with 10%aqueuos NaHCO₃ (10 ml), water (10 ml) and brine (10 ml), dried overMgSO₄ and concentrated in vacuo. Purification by kugelrohr distillationgave the title compound as a colorless oil.

PMR (CDCl₃): δ1.20 (6H, s), 1.43-1.55 (2H, m), 1.62-1.78 (2H, m), 2.60(2H, t, J=6.0 Hz), 7.10-7.41 (4H, m).

6-Bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F)

15.0 g (58.3 mmol) of 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)was cooled to 0° C. and then 2.8 ml of conc. H₂ SO₄ was added. Themixture was stirred for 2.5 hours, diluted with water (20 ml) andextracted with Et₂ O (3×40 ml). The combined organic layers were washedwith water, sat. aqueous NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. Purification by kugelrohr distillation gave thetitle compound as a colorless oil.

PMR (CDCl₃): δ1.25 (6H, s), 1.61-1.66 (2H, m), 1.74-1.82 (2H, m), 2.73(2H, t, J=6.0 Hz), 7.16-7.26 (3H, m).

7-Bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound G)

To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acidwas added a solution of 10 g (41.8 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125ml of benzene. The reaction mixture was stirred for 1 hour, quenchedwith ice cold water and extracted with Et₂ O (3×100 ml). The organiclayer was dried over MgSO₄, concentrated in vacuo, and purified bycolumn chromatography (silica, 10% EtOAc-hexane) to give the titlecompound as a white solid.

PMR (CDCl₃): δ1.28 (6H, s), 2.01 (2H, t, J=6.0 Hz), 2.72 (2H, t, J=6.0Hz), 7.31 (1H, d, J=9.0 Hz), 7.61 (1H, dd, J=3.0, 9.0 Hz), 8.11 (1H, d,J=3.0 Hz).

6-Bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound H)

Employing a published procedure (Mathur, N. C.; Snow, M. S. ; Young, K.M.; and Pincock, J. A. Tetrahedron, 41, 1509-1516 (1985)), ethyl4-(4-bromophenyl)butanoate (Compound C) was converted into the titlecompound. Alternatively, the title compound can be obtained usingsimilar reactions that were used to convert ethyl4-(3-bromophenyl)butanoate (Compound D) into7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1-(2H)-one (Compound G).

6-Ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K)

To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g(53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one(Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) ofbis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) ofcuprous iodide. The solution mixture was flushed with argon for 5minutes and then 100 ml (938.7 mmol) of trimethylsilyl acetylene wasadded. The reaction mixture was sealed in a pressure tube and placed ina preheated oil bath (100° C.) for 24 hours. The reaction mixture wasthen filtered through celite, washed with Et₂ O and the filtrateconcentrated in vacuo to give crude6-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one.To a solution of this crude TMS-acetylenic compound in 50 ml of methanolwas added 2.8 g (20.3 mmol) of K₂ CO₃. The mixture was stirred for 8hours at ambient temperature and then filtered. The filtrate wasconcentrated in vacuo, diluted with Et₂ O (100 ml), washed with water(10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO₄ andconcentrated in vacuo. Purification by column chromatography (silica,10% EtOAc-hexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ1.38 (6H, s), 2.01 (2H, t, J=7.1 Hz), 2.72 (2H, t, J=7.1Hz), 3.24 (1H, s), 7.39 (1H, dd, J=1.5, 8.1 Hz), 7.54 (1H, d, J=1.5 Hz),7.91 (1H, d, J=8.1 Hz).

7-Ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound L)

Employing the same general procedure as for the preparation of6-ethynyl-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one (Compound K), 7g (27.6 mmol) of 7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one(Compound G) was converted into the title compound using 39 ml (36.6mmol) of trimethylsilyl acetylene, 0.97 g (1.3 mmol) ofbis(triphenylphosphine)palladium(II) chloride, 0.26 g (1.3 mmol) ofcuprous iodide and 0.6 g (4.3 mmol) of K₂ CO₃.

PMR (CDCl₃): δ1.39 (6H, s), 2.02 (2H, t, J=7.0 Hz), 2.73 (2H, t, J=7.0Hz), 3.08 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.61 (1H, dd, J=1.8 , 8.2Hz), 8.14 (1H, d, J=9 1.8 Hz).

6-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethyl-naphthalene (CompoundO)

To a slurry of 12.2 g (79 mmol) of titanium trichloride in 150 ml of1,2-dimethoxyethane (DME) under argon atmosphere was added in smallportions 1.92 g (227 mmol) of lithium wire. The mixture was refluxed for1 hour, cooled to ambient temperature and then a mixture of 1.56 g (15.9mmol) of cyclohexanone and 1.0 g (3.97 mmol) of6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) in 50ml of DME was added. The resultant reaction mixture was stirred atambient temperature for 2 hours, refluxed for 16 hours, diluted withhexane (100 ml) and then filtered through florisil. Purification byflash chromatography (silica, 100% hexane) to give the title compound asa pale yellow oil.

PMR (CDCl₃): δ1.26 (6H, s), 1.52-1.64 (8H, br s), 2.30 (2H, t, J=5.5Hz), 2.42 (2H, t, J=5.5 Hz), 2.53 (2H, t, J=7.1 Hz), 7.04 (1H, d, J=8.2Hz), 7.23 (1H, dd, J=2.1 , 8.2 Hz), 7.41 (1H, d, J=2.1 Hz).

7-Bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound P)

Employing the same general procedure as for the preparation of6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound O), 1.0 g (3.97 mmol) of7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1-(2H)-one (Compound G) wasconverted into the title compound using 1.56 g (15.9 mmol) ofcyclohexanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

PMR (CDCl₃): δ1.23 (6H, s), 1.50-1.65 (8H, m), 2.33 (2H, br s), 2.45(2H, t, J=5.5 Hz), 2.50 (2H, t, J=7.1 Hz), 7.15 (d, J=8.1 Hz), 7.26 (1H,d, J=1.6 Hz), 7.29 (1H, br s).

6-Bromo-1-(3-pentylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound Q)

Employing the same general procedure as for the preparation of6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound O), 1.0 (3.97 mmol) of6-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1-(2H)-one (Compound H) wasconverted into the title compound using 1.37 g (15.9 mmol) of3-pentanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

PMR (CDCl₃): δ1.05 (3H, t, J=7.3 Hz), 1.13 (3H, t, J=7.2 Hz), 1.25 (6H,s), 1.64 (2H, t, J=7.1 Hz), 2.16-2.30 (4H, m), 2.50 (2H, t, J=7.1 Hz),7.09 (1H, d, J=8.2 Hz), 7.25 (1H, dd, J=2.1 , 8.2 Hz), 7.41 (1H, d,J=2.1 Hz).

7-Bromo-1-(3-pentylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound R)

Employing the same general procedure as for the preparation of6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound O), 1.0 g (3.97 mmol) of7-bromo-3,4-dihydro-4,4-dimethyl-naphthalen-1-(2H)-one (Compound G) wasconverted into the title compound using 1.37 g (15.9 mmol) of3-pentanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

PMR (CDCl₃): δ1.04 (3H, t, J=7.5 Hz), 1.14 (3H, t, J=7.5 Hz), 1.23 (6H,s), 1.63 (2H, t, J=7.1 Hz), 2.21 (2H, q, J=7.5 Hz), 2.29 (2H, q, J=7.5Hz), 2.49 (2H, t, J=7.1 Hz), 7.15 (1H, d, J=8.3 Hz), 7.29 (1H, dd, J=2.2, 8.3 Hz), 7.36 (1H, d, J=2.2 Hz).

6-Ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound U)

Employing the same general procedure as for the preparation of6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 530mg (1.66 mmol) of6-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound O) was converted into the title compound using 1.63 g (16.6mmol) of trimethylsilylacetylene, 20 mg (0.08 mmol) of cuprous iodide,60 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and40 mg (0.3 mmol) of potassium carbonate.

PMR (CDCl₃): δ1.26 (6H, s), 1.54-1.64 (8H, br s), 2.33 (2H, br s), 2.43(2H, t, J=5.9 Hz), 2.53 (2H, t, J=7.0 Hz), 3.07 (1H, s), 7.13 (1H, d,J=7.9 Hz), 7.27 (1H, dd, J=1.7, 7.9 Hz), 7.44 (1H, d, J=1.7 Hz).

7-Ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound V)

Employing the same general procedure as for the preparation of6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 351mg (1.1 mmol) of7-bromo-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound P) was converted into the title compound using 1.1 g (11 mmol)of trimethylsilylacetylene, 10 mg (0.04 mmol) of cuprous iodide, 38 mg(0.05 mmol) of bis(triphenylphosphine)palladium(II) chloride and 35 mg(0.25 mmol) of potassium carbonate.

PMR (CDCl₃): δ1.25 (6H, s), 1.50-1.67 (8H, m), 2.32 (2H, br s), 2.45(2H, t, J=5.9 Hz), 2.51 (2H, t, J=7.0 Hz), 3.00 (1H, s), 7.24 (1H, d,J=7.0 Hz), 7.29 (1H, d, J=1.8 Hz), 7.30 (1H, br s).

6-Ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene(Compound W)

Employing the same general procedure as for the preparation of6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 530mg (1.66 mmol) of6-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene(Compound Q) was converted into the title compound using 1.63 g (16.6mmol) of trimethylsilylacetylene, 20 mg (0.08 mmol) of cuprous iodide,60 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and40 mg (0.3 mmol) of potassium carbonate.

PMR (CDCl₃): δ1.04 (3H, t, J=7.6 Hz), 1.13 (3H, t, J=8.3 Hz), 1.24 (6H,s), 1.64 (2H, t, J=7.0 Hz), 2.15-2.32 (4H, m), 2.50 (2H, t, J=7.0 Hz),3.07 (1H, s), 7.18 (1H, d, J=8.0 Hz), 7.27 (1H, dd, J=1.7, 8.0 Hz), 7.43(1H, d, J=1.7 Hz).

7-Ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene(Compound X)

Employing the same general procedure as for the preparation of6-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound K), 384mg (1.25 mmol) of7-bromo-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene(Compound R) was converted into the title compound using 2.1 g (21 mmol)of trimethylsilylacetylene, 12 mg (0.06 mmol) of cuprous iodide, 43 mg(0.06 mmol) of bis(triphenylphosphine)palladium(II) chloride and 70 mg(0.5 mmol) of potassium carbonate.

PMR (CDCl₃): δ1.04 (3H, t, J=7.6 Hz), 1.13 (3H, t, J=7.4 Hz), 1.23 (6H,s), 1.63 (2H, t, J=7.0 Hz), 2.21 (2H, q, J=7.4 Hz), 2.27 (2H, q, J=7.6Hz), 2.48 (2H, t, J=7.0 Hz), 3.00 (1H, s), 7.23 (1H, d, J=8.0 Hz), 7.28(1H, dd, J=2.3, 8.0 Hz), 7.35 (1H, d, J=2.3 Hz).

Ethyl-4-iodobenzoate

To a suspension of 10 g (40.32 mmol) of 4-iodobenzoic acid in 100 mlabsolute ethanol was added 2 ml thionyl chloride and the mixture wasthen heated at reflux for 3 hours. Solvent was removed in vacuo and theresidue was dissolved in 100 ml ether. The ether solution was washedwith saturated NaHCO₃ and saturated NaCl solutions and dried (MgSO₄).Solvent was then removed in vacuo and the residue Kugelrohr distilled(100 degrees C.; 0.55 mm) to give the title compound as a colorless oil,PMR (CDCl₃): δ1.42 (3H, t, J˜7 Hz), 4,4 (2H, q, J˜7 Hz), 7.8 (4H).

Ethyl 6-chloronicotinate

A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol)ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 gdimethylaminopyridine in 200 ml methylene chloride was heated at refluxfor 2 hours. The mixture was allowed to cool, solvent removed in vacuoand the residue subjected to flash chromatography to give the titlecompound as a low-melting white solid. PMR (CDCl₃): δ1.44 (3H, t, J˜6.2Hz) 4.44 (2H, q, J˜4.4 Hz), 7.44 (1H, d, J˜8.1 Hz), 8.27 (1H, dd, J˜8.1Hz, 3 Hz), 9.02 (1H, d, J˜3 Hz).

6-Iodonicotinic acid

To 27.97 g (186.6 mmol) of sodium iodide cooled to -78° C. was added121.77 g (71.6 ml, 952.0 mmol) of hydriodic acid (57 wt %). The reactionmixture was allowed to warm slightly with stirring for 5 minutes, andthen 30.00 g (190.4 mmol) of 6-chloronicotinic acid was added. Theresulting mixture was allowed to warm to room temperature with stirringand then heated at 120°-125° C. in an oil bath for 42 hours. A darkbrown layer formed above the yellow solid material. The reaction mixturewas allowed to cool to room temperature and then poured into acetone(chilled to 0° C.). The resultant yellow solid was collected byfiltration, washed with 200 ml of 1N NaHSO₃ solution, and dried in highvacuum (3 mm Hg) to give the title compound as a pale yellow solid.

PMR (DMSO-d₆): δ7.90 (1H, dd, J=8.1, 2 Hz), 7.99 (1H, d, J=8.1 Hz), 8.80(1H, d, J=2.Hz).

Ethyl 6-iodonicotinate

To a suspension of 23.38 g (94.2 mmol) of 6-iodonicotinic acid in 100 mlof dichloromethane was added a solution of 19.86 g (103.6 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 250 ml ofdichloromethane. To this suspension was added 12.40 g (15.8 ml, 269.3mmol) of ethanol (95%) and 1.15 g (9.4 mmol) of 4-dimethylaminopyridine.The resulting solution mixture was then heated at 50° C. in an oil bathfor 24.5 hours, concentrated in vacuo, partitioned between 200 ml ofwater and 250 ml of ethyl ether, and the layers were separated. Theaqueous phase was washed with 2×150 ml-portions of ethyl ether. Allorganic phases were combined, washed once with 75 ml of brine solution,dried over MgSO₄, filtered and concentrated in vacuo to a yellow solid.Purification by flash chromatography (silica, 10% ethyl acetate inhexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ1.41 (3H, t, J=7.1 Hz), 4.41 (2H, q, J=7.1 Hz), 7.85 (1H,d, J=8.2 Hz), 7.91 (1H, dd, J=8.2, 2.1 Hz), 8.94 (1H, d, J=2.1 Hz).

Ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1)

To a solution of 8.8 g (47.8 mmol) of6-ethynyl-1,2,3,4-tetrahydro-4,4-dimethylnaphthalen-1-one (Compound K)flushed for 15 minutes with a stream of argon, and 13.2 g (47.8 mmol) ofethyl 4-iodobenzoate in 200 ml of triethylamine was added 1.1 g (1.6mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.30 g (1.6mmol) of cuprous iodide. The solution mixture was flushed with argon for5 minutes and then stirred at ambient temperature for 18 hours. Thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo. Purification by flash chromatography (silica, 10%EtOAc-hexane) yielded the title compound as a white solid.

PMR (CDCl₃): δ1.41 (3H, t, J=7.2 Hz), 1.43 (6H, s), 2.04 (2H, t, J=7.0Hz), 2.75 (2H, t, J=7.0 Hz), 4.40 (2H, q, J=7.2 Hz), 7.46 (1H, dd,J=1.5, 8.1 Hz), 7.60 (1H, d, J=1.5 Hz), 7.63 (2H, d, J=8.4 Hz), 8.01(1H, d, J=8.1 Hz), 8.05 (2H, d, J=8.4 Hz).

Ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate(Compound 2)

Employing the same general procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1), 4 g (21.7 mmol) of7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound L) wasconverted into the title compound using 6 g (21.7 mmol) of ethyl4-iodobenzoate, 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II)chloride and 1.4 g (7.2 mmol) of cuprous iodide.

PMR (CDCl₃): δ1.41 (3H, t, J=7.2 Hz), 1.41 (6H, s), 2.04 (2H, t, J=6.5Hz), 2.76 (2H, t, J=6.5 Hz), 4.40 (2H, q, J=7.2 Hz), 7.44 (1H, d, J=8.2Hz), 7.59 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=1.8, 8.2 Hz), 8.04 (2H, d,J=8.4 Hz), 8.15 (1H, d, J=1.8 Hz).

4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoicacid (Compound 7)

To a suspension of 0.30 g (0.87 mmol) of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1) in 4 ml of THF and 2 ml of ethanol was added 2 ml (2 mmol)of LiOH (1N aqueous solution). The reaction mixture was stirred at roomtemperature for 4 hours, concentrated in vacuo to near dryness,partitioned between EtOAc and 1 ml of water and acidified to pH 4 with10% HCl. The aqueous layer was extracted with EtOAc and then the organiclayer was dried over Na₂ SO₄ and concentrated in vacuo to give the titlecompound as a light yellow solid.

PMR (DMSO-d₆): δ1.39 (6H, s), 1.98 (2H, t, J=7.0 Hz), 2.70 (2H, t, J=7.0Hz), 7.54 (1H, dd, J=1.5, 8.1 Hz), 7.73 (2H, d, J=8.4 Hz), 7.77 (1H, d,J=1.5 Hz), 7.90 (1H, d, J=8.1 Hz), 8.00 (2H, d, J=8.4 Hz).

Ethyl4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 113)

To a refluxing solution of 1.00 g (15.30 mmol) of 20 mesh, granular zinc(activated prior to use by washing with 2% HCl , water, 95% ethanol,acetone, anhydrous Et₂ O and then dried in vacuum for several hours) in20 ml of dry benzene was slowly added a mixture of 0.23 ml (1.62 mmol)of ethyl bromoacetate, 0.28 g (0.81 mmol) of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1) in 10 ml of dry benzene. The resulting mixture was refluxedfor 2 hours, cooled to room temperature and the precipitate filteredthrough celite. The filtrate was washed with cold 15% H₂ SO₄, sat.aqueous NaHCO₃ and brine. The organic phase was dried over Na₂ SO₄ andconcentrated in vacuo to a yellow oil. Purification by flashchromatography (silica, 10% EtOAc-hexane) yielded the title compound asa light yellow solid.

PMR (CDCl₃) δ: 1.30 (6H, s), 1.42 (3H, t, J=7.1 Hz), 1.75 (2H, m), 2.08(2H, m), 2.77 (2H, s), 4.22 (3H, m), 4.39 (2H, q, J=7.1 Hz), 7.38 (1H,dd, J=1.7 , 6.5 Hz), 7.49 (1H, d, J=1.6 Hz), 7.59 (3H, m), 8.02 (2H, d,J=8.4 Hz).

Ethyl4-[7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 114) and Ethyl4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate(Compound 115)

To a solution of 0.50 g (1.15 mmol) of ethyl4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 113) in 25 ml of dry benzene was added 2.12 g (8.90 mmol) of(methoxy carbonylsulfamoyl)triethyl ammonium hydroxide (BurgessReagent). The reaction mixture was heated at 50° C. for 30 minutes,cooled to room temperature and concentrated in vacuo. The residue wasdiluted with EtOAc, washed with water and brine, dried over Na₂ SO₄ andconcentrated in vacuo to an oil. Purification by flash chromatography(silica, 25% EtOAc-hexane) yielded the title compounds as solids in aratio of 5 to 1, respectively.

Ethyl4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 114):

PMR (CDCl₃) δ1.17 (3H, t, J=2.8 Hz), 1.30 (6H, s), 1.41 (3H, t, J=7.1Hz), 2.26 (2H, d, J=4.6 Hz), 3.46 (2H, s), 4.12 (2H, q, J=7.2 Hz), 4.38(2H, q, J=7.1 Hz), 5.96 (1H, s), 7.17 (1H, d, J=8.0 Hz), 7.36 (1H, dd,J=1.7, 6.4 Hz), 7.48 (1H, d, J=1.7 Hz), 7.58 (2H, d, J=6.5 Hz), 8.01(2H, d, J=6.5 Hz).

Ethyl4-[(5-carboethoxymethylidene-7,8,-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate(Compound 115):

PMR (CDCl₃) δ1.32 (6H, s), 1.41 (3H, t, J=7.1 Hz), 1.73 (3H, t, J=6.7Hz), 3.22 (2H, m), 4.22 (2H, q, J=7.1 Hz), 4.39 (2H, q, J=7.1 Hz), 6.30(1H, d, J=1.8 Hz), 7.35 (1H, dd, J=1.7, 6.6 Hz), 7.55 (1H, d, J=1.6 Hz),7.60 (3H, dd, J=2.0, 6.4 Hz), 8.04 (2H, d, J=6.5 Hz).

(Trimethylsilyl)ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 116)

To a solution of 0.24 g (0.73 mmol) of4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoicacid (Compound 7) in 10 ml of dry CH₂ Cl₂ was added 0.09 g (0.74 mmol)of dimethylaminopyridine, 0.115 ml (0.80 mmol) of trimethylsilylethanoland 0.17 g (0.88 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride. The reaction mixture was stirred at 25° C. for 5 hours,washed with sat. aqueous NaHCO₃ and brine, dried over Na₂ SO₄ andconcentrated in vacuo to an oil. Purification by flash chromatography(silica, 10% EtOAc-hexane) yielded the title compound as a white solid.

PMR (CDCl₃) δ: 0.09 (9H, s), 1.14 (2H, m), 1.42 (6H, s), 2.03 (2H, t,J=7.1 Hz), 2.74 (2H, t, J=6.5 Hz), 4.43 (2H, t, J=8.5 Hz), 7.45 (1H, dd,J=1.5, 6.7 Hz), 7.61 (3H, d, J=7.0 Hz), 8.03 (3H, t, J=6.7 Hz).

Trimethylsilylethyl4-[(5,6,7,8,-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 117)

Employing the same general procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 113), 0.38 g (0.89 mmol) of trimethylsilylethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 116), was converted into the title compound (yellow solid)using 0.50 g (7.65 mmol) of zinc, 0.20 ml (1.78 mmol) of ethylbromoacetate and 20 ml of dry benzene.

PMR (CDCl₃) δ: 0.09 (9H, s), 1.14 (2H, m), 1.28 (8H, m), 1.74 (2H, m),2.07 (2H, m), 2.77 (2H, s), 4.20 (3H, m), 4.42 (3H, t, J=8.4 Hz), 7.37(1H, dd, J=1.6, 6.7 Hz), 7.49 (1H, s), 7.58 (3H, dd, J=3.8, 7.0 Hz),8.01 (2H, d, J=8.4 Hz).

4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoicacid (Compound 118)

To a solution of 0.25 g (0.49 mmol) of trimethylsilylethyl4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxy-methylnaphth-2-yl)ethynyl]benzoate(Compound 117) in 5 ml of dry THF (flushed with argon) was added 1.48 ml(1.5 mmol) of tetrabutyl ammonium fluoride (1M solution in THF). Thereaction mixture was stirred at room temperature for 12 hours,concentrated in vacuo to an oil and slowly diluted with water. Thesolution was acidified to pH 4 with 10% HCl and extracted with Et₂ O.The organic layer was dried over Na₂ SO₄, concentrated in vacuo to anoil and purified by flash chromatography (silica, 90% EtOAc-hexane) togive the title compound as a white solid.

PMR (CDCl₃) δ: 1.30 (9H, m), 1.72 (2H, m), 2.08 (2H, m), 2.78 (2H, s),4.21 (2H, q, J=7.0 Hz), 7.38 (1H, dd, J=1.5, 6.6 Hz), 7.50 (1H, s), 7.58(1H, d, J=8.2 Hz), 7.62 (2H, d, J=8.4 Hz), 8.10 (2H, d, J=8.4 Hz).

Ethyl4-[(5-hydroxy-8,8-dimethyl-5-carboethoxymethyl-5,6,7,8-tetrahydronapth-3-yl)ethynyl]benzoate(Compound 119)

Employing the same general procedure as for the preparation of ethyl4-[(7,8-dihydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 113), 1.00 g (2.88 mmol) of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate(Compound 2) was converted into the title compound (light yellow solid)using 1.00 g (15.30 mmol) of zinc, 0.639 ml (5.76 mmol) of ethylbromoacetate and 70 ml of dry benzene.

PMR (CDCl₃) δ: 1.30 (9H, m), 1.40 (3H, t, J=7.1 Hz), 1.75 (2H, m), 2.04(2H, m), 2.80 (2H, d, J=3.1 Hz), 4.21 (2H, m), 4.38 (2H, q, J=7.2 Hz),7.30 (1H, d, J=8.3 Hz), 7.41 (1H, dd, J=1.8, 6.4 Hz), 7.57 (2H, d, J=6.7Hz), 7.81 (1H, d, J=1.8 Hz), 8.03 (2H, d, J=8.4 Hz).

Ethyl4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl]benzoate(Compound 120) and Ethyl4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate(Compound 121)

Employing the same general procedure as for the preparations of ethyl4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-2-yl)ethynyl]benzoate(Compound 114) and ethyl4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate(Compound 115), 0.57 g (1.31 mmol) of ethyl4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl]benzoate(Compound 119) was converted into the title compounds (yellow solid andwhite solid, respectively) using 15 ml of dry benzene, 6 ml of dry THFand 2.42 g (10.1 mmol) of (methoxy carbonylsulfamoyl)triethyl ammoniumhydroxide (Burgess Reagent).

Ethyl4-[(7,8-dihydro-8,8-dimethyl-5-carboethoxymethylnaphth-3-yl)ethynyl]benzoate(Compound 120):

PMR (CDCl₃) δ1.22 (3H, t, J=7.1 Hz), 1.29 (6H, s), 2.70 (2H, d, J=4.4Hz), 3.49 (2H, s), 4.17 (2H, q, J=7.1 Hz), 4.00 (2H, q, J=7.1 Hz), 5.96(1H, t, J=4.5 Hz), 7.35 (3H, m), 7.58 (2H, d, J=8.4 Hz), 8.02 (2H, d,J=7.9 Hz).

Ethyl4-[(5-carboethoxymethylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate(Compound 121):

PMR (CDCl₃) δ1.31 (9H, m), 1.74 (2H, q, J=6.7 Hz), 3.24 (2H, t, J=3.3Hz), 4.22 (2H, q, J=7.1 Hz), 4.40 (2H, q, J=7.1 Hz), 6.33 (1H, s), 7.37(1H, d, J=7.9 Hz), 7.50 (1H, d, J=8.3 Hz), 7.59 (2H, d, J=7.7 Hz), 7.79(1H, s), 8.04 (2H, d, J=8.4 Hz).

Ethyl4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate(Compound 131)

Employing the same general procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1), 289 mg (1.22 mmol) of6-ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound U) was converted into the title compound using 337 mg (1.22mmol) of ethyl 4-iodobenzoate, 77 mg (0.4 mmol) of cuprous iodide and286 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride.

PMR (CDCl₃): δ1.28 (6H, s), 1.38 (3H, t, J=7.1 Hz), 1.54-1.65 (8H, brs), 2.32 (2H, br s), 2.46 (2H, t, J=6.4 Hz), 2.51 (2H, t, J=7.1 Hz),4.37 (2H, q, J=7.1 Hz), 7.16 (1H, d, J=8.0 Hz), 7.29 (1H, dd, J=1.7, 8.0Hz), 7.47 (1H, d, J=1.7 Hz), 7.57 (2H, d, J=8.3 Hz), 8.00 (2H, d, J=8.3Hz).

Ethyl4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate(Compound 132)

Employing the same general procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1), 289 mg (1.22 mmol) of7-ethynyl-1(2H)-cyclohexylidene-3,4-dihydro-4,4-dimethylnaphthalene(Compound V) was converted into the title compound using 337 mg (1.22mmol) of ethyl 4-iodobenzoate, 77 mg (0.4 mmol) of cuprous iodide and286 mg (0.41 mmol) of bis(triphenylphosphine)palladium(II) chloride.

PMR (CDCl₃): δ1.27 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.52-1.69 (8H, m),2.33 (2H, br s), 2.46 (2H, t, J=6.2 Hz), 2.53 (2H, t, J=7.4 Hz), 4.38(2H, q, J=7.1 Hz), 7.27 (1H, d, J=8.5 Hz), 7.33 (2H, m), 7.56 (2H, d,J=8.4 Hz), 8.00 (2H, d, J=8.4 Hz).

Ethyl4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-2-yl)ethynyl]benzoate(Compound 133)

Employing the same general procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1), 143 mg (0.57 mmol) of6-ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene(Compound W) was converted into the title compound using 142 mg (0.51mmol) of ethyl 4-iodobenzoate, 36 mg (0.19 mmol) of cuprous iodide and130 mg (0.19 mmol) of bis(triphenylphosphine)palladium(II) chloride.

PMR (CDCl₃): δ1.05 (3H, t, J=7.4 Hz), 1.13 (3H, t, J=7.3 Hz), 1.27 (6H,s), 1.40 (3H, t, J=7.1 Hz), 1.65 (2H, t, J=6.9 Hz), 2.17-2.32 (4H, m),2.51 (2H, t, J=6.9 Hz), 4.38 (2H, q, J=7.1 Hz), 7.21 (1H, d, J=8.0 Hz),7.32 (1H, dd, J=1.7, 8.0 Hz), 7.47 (1H, d, J=1.7 Hz), 7.58 (2H, d, J=8.2Hz), 8.02 (2H, d, J=8.2 Hz).

Ethyl4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)-naphth-3-yl)ethynyl]benzoate(Compound 134)

Employing the same general procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1), 235 mg (0.94 mmol) of7-ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene(Compound X) was converted into the title compound using 236 mg (0.85mmol) of ethyl 4-iodobenzoate, 57 mg (0.3 mmol) of cuprous iodide and220 mg (0.31 mmol) of bis(triphenylphosphine)palladium(II) chloride.

PMR (CDCl₃): δ1.07 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.5 Hz), 1.25 (6H,s), 1.40 (3H, t, J=7.1 Hz), 1.65 (2H, t, J=7.0 Hz), 2.22 (2H, q, J=7.5Hz), 2.31 (2H, q, J=7.5 Hz), 2.50 (2H, t, J=7.0 Hz), 4.38 (2H, q, J=7.1Hz), 7.28 (1H, d, J=8.0 Hz), 7.35 (1H, dd, J=1.7, 8.0 Hz), 7.39 (1H, d,J=1.7 Hz), 7.56 (2H, d, J=8.5 Hz), 8.01 (2H, d, J=8.5 Hz).

4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoicacid (Compound 135)

Employing the same general procedure as for the preparation of4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoicacid (Compound 7), 95 mg (0.23 mmol) of ethyl4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate(Compound 131 was converted to the title compound using 1 ml (1 mmol) ofLiOH (1M aqueous solution).

PMR (CDCl₃): δ1.24 (6H, s), 1.50-1.61 (8H, br s), 2.30 (2H, br s), 2.39(2H, br s), 2.47 (2H, br s), 7.16 (1H, d, J=8.1 Hz), 7.34 (1H, dd,J=1.7, 8.1 Hz), 7.48 (1H, d, J=1.7 Hz), 7.65 (2H, d, J=8.4 Hz), 7.96(2H, d, J=8.4 Hz).

4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoicacid (Compound 136)

Employing the same general procedure as for the preparation of4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoicacid (Compound 7), 95 mg (0.23 mmol) of ethyl4-[(5(6H)-cyclohexylidene-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate(Compound 132) was converted to the title compound using 1 ml (1 mmol)of LiOH (1M aqueous solution).

PMR (Acetone-d₆): δ1.27 (6H, s), 1.50-1.70 (8H, m), 2.33 (2H, br s),2.49 (2H, br s), 2.53 (2H, t, J=7.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.35(2H, br s), 7.61 (2H, d, J=8.1 Hz), 8.08 (2H, d, J=8.1 Hz).

4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-2-yl)ethynyl]benzoicacid (Compound 137)

Employing the same general procedure as for the preparation of4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoicacid (Compound 7), 90 mg (0.23 mmol) of ethyl4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-2-yl)ethynyl]benzoate(Compound 133) was converted to the title compound using 0.5 ml (0.5mmol) of LiOH (1M aqueuos solution).

PMR (CDCl₃): δ1.05 (3H, t, J=7.6 Hz), 1.34 (3H, t, J=7.4 Hz), 1.27 (6H,s), 1.67 (2H, t, J=7.1 Hz), 2.20-2.34 (4H, m), 2.54 (2H, t, J=7.1 Hz),7.27 (1H, d, J=7.9 Hz), 7.36 (1H, dd, J=1.7, 7.9 Hz), 7.53 (1H, d, J=1.7Hz), 7.66 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.4 Hz).

4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-3-yl)ethynyl]benzoicacid (Compound 138)

Employing the same general procedure as for the preparation of4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoicacid (Compound 7), 90 mg (0.23 mmol) of ethyl4-[(7,8-dihydro-8,8-dimethyl-5(6H)-(3-pentylidene)naphth-3-yl)ethynyl]benzoate(Compound 134) was converted to the title compound using 1 ml (1.0 mmol)of LiOH (1M aqueous solution).

PMR (CDCl₃): δ1.05 (3H, t, J=7.6 Hz), 1.16 (3H, t, J=7.5 Hz), 1.25 (6H,s), 1.65 (2H, t, J=6.9 Hz), 2.22 (2H, q, J=7.5 Hz), 2.31 (2H, q, J=7.6Hz), 2.50 (2H, t, J=6.9 Hz), 7.28 (1H, d, J=8.1 Hz), 7.36 (1H, dd,J=1.7, 8.1 Hz), 7.41 (1H, d, J=1.7 Hz), 7.61 (2H, d, J=8.5 Hz), 8.08(2H, d, J=8.5 Hz).

Ethyl4-[[7,8-dihydro-8,8-dimethyl-5(E)(6H)-(cyanomethylidene)naphth-2-yl]ethynyl]benzoate(Compound 145)

Ethyl4-[[7,8-dihydro-8,8-dimethyl-5(Z)(6H)-(cyanomethylidene)naphth-2-yl]ethynyl]benzoate(Compound 146)

To a cold solution (0° C.) of 442 mg (2.5 mmol) of diethylcyanomethylphosphonate in 8 ml of THF was added 450 mg (2.25 mmol) ofpotassium bis(trimethylsilyl)amide. The mixture was stirred for 15minutes and then a solution of 366 mg (1.08 mmol) ofethyl-4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate(Compound 1) in 7 ml of THF was added via syringe. The mixture wasstirred for 8 hours, diluted with Et₂ O (100 ml), washed with water (10ml) and brine (10 ml), dried over MgSO₄ and concentrated in vacuo.Purification by chromatography (silica, 5% EtOAc-hexane) gave a 6:1ratio of E:Z isomers. Separation by normal phase HPLC (Partisil 10, 5%EtOAc-hexane) gave the title compounds (RT=64 minutes and 70 minutes),respectively.

Ethyl4-[[7,8-dihydro-8,8-dimethyl-5(E)(6H)-(cyanomethylidene)naphth-2-yl]ethynyl]benzoate(Compound 145):

PMR (CDCl₃): (RT=64 minutes) δ1.35 (6H, s), 1.41 (3H, t, J=7.1 Hz), 1.82(2H, t, J=6.4 Hz), 2.94 (2H, t, J=6.4 Hz), 4.39 (2H, q, J=7.1 Hz), 5.72(1H, d, J=1.7 Hz), 7.36 (1H, dd, J=1.6 , 8.3 Hz), 7.50 (1H, d, J=8.3Hz), 7.58 (1H, d, J=1.6 Hz), 7.61 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.4Hz).

Ethyl4-[[7,8-dihydro-8,8-dimethyl-5(Z)6(H)-(cyanomethylidene)naphth-2-yl]ethynyl]benzoate(Compound 146):

PMR (CDCl₃): (RT=70 minutes) δ1.35 (6H, s), 1.42 (3H, t, J=7.1 Hz), 1.84(2H, t, J=6.5 Hz), 2.64 (2H, t, J=6.5 Hz), 4.40 (2H, q, J=7.1 Hz), 5.32(1H, d, J=1.4 Hz), 7.43 (1H, dd, J=1.6, 8.2 Hz), 7.57 (1H, d, J=1.6 Hz),7.62 (2H, d, J=8.4 Hz), 8.05 (2H, d, J=8.4 Hz), 8.18 (2H, d, J=8.2 Hz).

What is claimed is:
 1. A compound of the formula ##STR11## wherein R₁ ishydrogen or alkyl of 1 to 10 carbons; R₂ and R₃ are hydrogen, or alkylof 1 to 6 carbons and the substituted ethynyl group occupies either the2 or the 3 position of the tetrahydronaphthalene nucleus;m is an integerhaving the value of 0-3; o is an integer having the value 0-4; Y isheteroaryl selected from a group consisting of pyridyl, thienyl, furyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, andimidazolyl, said groups being optionally substituted with one or two R₂groups; A is (CH₂)_(n) where n is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds; B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO,CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, or tri-loweralkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or(trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenol or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons, and R₁₉is independently hydrogen, alkyl of 1 to 10 carbons, fluoro-substitutedalkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl, C₁ -C₁₀-alkylphenyl, naphthyl, C₁ -C₁₀ -alkylnaphthyl, phenyl-C₁ -C₁₀ alkyl,naphthyl-C₁ -C₁₀ alkyl; CN, CHO, CH(OR₁₂)₂, CHOR₁₃ O, (CH₂)_(p) CO₂ R₈(CH₂)_(p) CH₂ OH, (CH₂)_(p) CH₂ OR₁₁, (CH₂)_(p) CH₂ OCOR₁₁, where p isan integer between 0 to 10, or the two R₁₉ groups jointly represent 3 to6 methylene groups which together with the alkylidene carbon complete aring.
 2. A compound of claim 1 where Y is pyridyl, thienyl or furyl. 3.A compound of claim 1 where Y is pyridyl.
 4. A compound of claim 3 wherethe pyridyl ring is substituted in the 2 and 5 positions.
 5. A compoundof claim 1 where Y is thienyl or furyl.
 6. A compound of claim 1 whereR₂ is hydrogen.
 7. A compound of claim 1 where R₃ is hydrogen.
 8. Acompound of claim 1 where R₁₉ is hydrogen, alkyl of 1 to 10 carbons,cyano (CN), COOR₈, or the two R₁₉ groups jointly form a --(CH₂)_(q)radical where q is an integer having the values of 3 to
 7. 9. A compoundof the formula ##STR12## wherein R₁ is hydrogen or alkyl of 1 to 10carbons; R₂ and R₃ are hydrogen, or alkyl of 1 to 6 carbons and thesubstituted ethynyl group occupies either the 2 or the 3 position of thetetrahydronaphthalene nucleus;m is an integer having the value of 0-3; ois an integer having the value 0-4; Y is pyridyl optionally substitutedwith one or two R₂ groups; A is (CH₂)_(n) where n is 0-5, lower branchedchain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenylhaving 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbonsand 1 or 2 triple bonds; B is hydrogen, COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, CONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O, --COR₇, CR₇ (OR₁₂)₂, CR₇ OR₁₃ O, ortri-lower alkylsilyl, where R₇ is an alkyl, cycloalkyl or alkenyl groupcontaining 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons or(trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons, and R₁₉is independently hydrogen, alkyl of 1 to 10 carbons, CN, CH₂ CO₂ R₈ orthe two R₁₉ groups jointly represent 3 to 6 methylene groups whichtogether with the alkylidene carbon complete a ring.
 10. A compound ofclaim 9 where A is (CH₂)_(n) where n is 0-5 and where B is COOH or apharmaceutically acceptable salt thereof, COOR₈, or CONR₉ R₁₀.
 11. Acompound of the formula ##STR13## wherein X₂ is N; R₈ is hydrogen, analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons;R_(19') is H, cyano (CN) or lower alkyl, andR_(19") is H, cyano (CN) or lower alkyl, or the R_(19') and R_(19")groups jointly form a --(CH₂)₅ -- group, and the substituted ethynylgroup occupies the 2 or 3 position of the tetrahydronaphthalene nucleus.12. A compound of claim 11 where the R_(19') and R_(19") groups jointlyform a --(CH₂)₅ -- group.
 13. A compound of claim 12 where R₈ is H or C₂H₅.
 14. A compound of claim 11 where the R'₁₉ is CO₂ C₂ H₅ and R"₁₉ isH.
 15. A compound of claim 14 where R₈ is H or C₂ H₅.
 16. A compound ofclaim 11 where the R_(19') is C₂ H₅ and R_(19") is C₂ H₅.
 17. A compoundof claim 16 where R₈ is H or C₂ H₅.
 18. A compound of claim 11 where oneof the R_(19') and R_(19") groups is cyano (CN) and the other is H. 19.A compound of claim 18 where R₈ is H or C₂ H₅.